Systemic lupus erythematosus (SLE) is a potentially fatal, multifactorial chronic autoimmune disease. The disease profile of SLE is highly diverse, and is affected by environmental contributions as well as varied genetic factors. Despite the heterogeneity in disease severity and pathogenic mechanisms in SLE, recent studies have indicated that the most robust transcriptional biomarkers of disease progression are signatures of increased B cell activation/differentiation and increased type I interferon production. Therapies targeting these central markers of disease pathogenicity are particularly promising research areas. Importantly, pathways mediating B cell activation, B cell differentiation, and type I interferon release share a common component, Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6). Defective negative regulation of TRAF6 signaling is seen in SLE, and the role of TRAF6 as a regulator central to the major cellular processes in SLE pathogenicity highlights TRAF6 as a critical therapeutic target. Progenra proposes to validate and perform a high throughput screening campaign to identify novel and selective small molecule TRAF6 inhibitors. Progenra?s diverse library of 350,000 small molecules and established experience in discovery of ubiquitin ligase inhibitors provides a strong developmental platform to identify these molecules. Cellular proof of concept assays will be conducted on selected hits to evaluate their effect TRAF6-dependent signaling pathways, including type I interferon secretion, TLR7-mediated NF?B activation, and expression of the transcriptional regulator of type I interferon factor, IFN7. Small molecule TRAF6 inhibitors will decrease type I interferon signaling and B cell activation, cellular processes related to SLE pathogenesis. Thus, TRAF6 inhibition allows selective inhibition of inflammatory signaling mechanisms specific to the disease progression of SLE.